Pharmacological inhibition of HDAC6 overcomes cisplatin chemoresistance by targeting cancer stem cells in oral squamous cell carcinoma

Abstract

Background Chemoresistance is associated with recurrence and metastasis in oral squamous cell carcinoma (OSCC). The cancer stem cell (CSC) subpopulation is highly resistant to therapy, and they are regulated by epigenetic mechanisms. HDACs are histone deacetylase enzymes that epigenetically regulate gene expression. HDAC6 acts on several physiological processes, including oxidative stress, autophagy and DNA damage response, and its accumulation is associated with cancer. Here, we investigate the role of HDAC6 in CSC‐mediated chemoresistance in oral carcinoma in addition to its application as a therapeutic target to reverse chemoresistance. Methods Wild‐type oral carcinoma cell lines (CAL27 WT and SCC9 WT), cisplatin‐resistant (CAL27 CisR and SCC9 CisR), and the subpopulations of cancer stem cells (CSC+) and non‐stem (CSC−) derived from CisR cells were investigated. HDAC6 accumulation was analyzed by Western blot and immunofluorescence; DNA damage was evaluated by immunofluorescence of phospho‐H2A.X; the qPCR for PRDX2, PRDX6, SOD2, and TXN and ROS assay assessed oxidative stress. Apoptosis and CSC accumulation were investigated by flow cytometry. Results We identified the accumulation of HDAC6 in CisR cell lines and CSC. Cisplatin‐resistant cell lines and CSC demonstrated a reduction in DNA damage and ROS and elevated expression of PRDX2. The administration of tubastatin A (a specific HDAC6 inhibitor) increased oxidative stress and DNA damage and decreased PRDX2. Tubastatin A as a monotherapy induced apoptosis in CisR and CSC and reduced the stemness phenotype. Conclusion High levels of HDAC6 sustain CSC subpopulation and chemoresistance in OSCC, suggesting HDAC6 as a pharmacological target to overcome resistance and perhaps prevent recurrence in OSCC.

Chemotherapeutic Drug Resistance Associated with Differential miRNA Expression of miR-375 and miR-27 among Oral Cancer Cell Lines

“…Due to the expanding evidence that miRNAs are associated with chemotherapy resistance, the overall goal of this project was to evaluate both oral cancer resistance and miRNA expression to determine whether significant relationships could be identified. The results of this study clearly demonstrated at least two oral cancer cell lines (SCC9 and SCC25) with significant resistance to all three main chemotherapies (Cisplatin, 5-FU and Taxol), confirming recent observations made in other studies of chemotherapy resistance [ 29 , 30 , 31 , 32 ]. These data contribute to a body of important research that seeks to identify model systems for evaluating the mechanisms responsible for chemotherapy resistance among oral cancers [ 33 ].…”

HDAC6 inhibitor promotes reactive oxygen species‐meditated clearance of Staphylococcus aureus in macrophage

“…41 When using LPS to stimulate primary bovine mammary epithelial cells, HDAC6 overexpression significantly induced ROS generation. 42 These contrasting results may be because of the different cell types used in the experiments because, in cancer stem cells, the administration of TubA increases ROS accumulation, 43 consistent with our findings. In addition, ROS can be produced by the activation of NADPH (NOX2) or mitochondria.…”

Targeting histone deacetylases in head and neck squamous cell carcinoma: molecular mechanisms and therapeutic targets

“…Furthermore, HDAC6 has been implicated in autophagy and served as a critical regulator of cytoprotective response, bridging the connection between autophagy and Mubiquitin-proteasome system, mediating regulation between endoplasmic reticulum (ER) stress, autophagy and conferring chemoresistance in HNSCC [74]. Elevated levels of HDAC6 contributed to chemotherapy resistance in OSCC, making it a potential target for overcoming chemoresistance and preventing recurrence [75]. HDAC6 accumulation in cisplatin-resistant OSCC cells inhibited cell apoptosis by reducing reactive oxygen species (ROS) levels, diminishing DNA damage and increasing recombinant peroxiredoxin 2 (PRDX2) expression [75].…”

“…Elevated levels of HDAC6 contributed to chemotherapy resistance in OSCC, making it a potential target for overcoming chemoresistance and preventing recurrence [75]. HDAC6 accumulation in cisplatin-resistant OSCC cells inhibited cell apoptosis by reducing reactive oxygen species (ROS) levels, diminishing DNA damage and increasing recombinant peroxiredoxin 2 (PRDX2) expression [75].…”